Process Development Handbook

Citra Labs
Process
Development
Handbook
Citra Labs, LLC, a Biomet Biologics Company
55 Messina Drive | Braintree, MA 02184 USA
1-800-299-3411
2
Table of Contents
Introduction.................................................................................................................................................4
Overview.........................................................................................................................................................5
Indications for Use (IFU).............................................................................................................................6
Sample Standard Operating Procedures.......................................................................................8
Rejuvenation Prior to Immediate Use...................................................................................................9
Rejuvenation Prior to Cryopreservation.............................................................................................12
Training & Competency Assessment..............................................................................................15
Training Checklist........................................................................................................................................16
Product Quiz................................................................................................................................................17
FDA Approval Statement.................................................................................................................... 18
Process Validation & Control............................................................................................................ 20
ISBT Labeling............................................................................................................................................ 22
Frequently Asked Questions............................................................................................................ 24
Appendix A—Materials and Equipment Checklist................................................................ 28
Appendix B—Training Presentation............................................................................................. 29
Product Quiz Answer Key................................................................................................................... 29
rejuvesol™ is a trademark of Biomet Biologics.
ADSOL® is a registered trademark of Fenwal, Inc.
Manufactured for: Citra Labs, LLC
55 Messina Drive, Braintree, MA 02184 USA
1-800-299-3411 · Fax 781-848-6781
Manufactured by: Grand River Aseptic Manufacturing, Inc.
140 Front Ave SW, Suite 3 Grand Rapids, MI 49504 USA
Introduction
4
Introduction
Overview
This rejuvesol™ red blood cell solution Process Development Handbook is a complete
package designed for training and implementation by Citra Labs and Biomet Biologics
team members for primary institution-based trainers and customers.
Information contained herein may be used for the development of appropriate
documentation that includes sample Standard Operating Procedures (SOPs),
documents to facilitate staff training and competency and information pertinent to
validation when using rejuvesol Solution according to approved indications for use.
This document is not intended, and should not be used, to address specific regulatory
requirements of any blood establishment.
5
Introduction
Indications for Use (IFU)
rejuvesol red blood cell processing solution (PN 7012) for use in the
Extracorporeal Rejuvenation of Red Blood Cell (50 mL Glass Vial)
Description
rejuvesol red blood cell processing solution (rejuvesol
Solution) is a sterile, non-pyrogenic solution of pyruvate,
inosine, adenine, and phosphate in Water for Injection
intended only for use in the extracorporeal rejuvenation
of a unit of red blood cell (RBC) concentrate. Each 50 mL
of rejuvesol Solution contains sodium pyruvate 0.550 g,
inosine 1.34 g, adenine 0.034 g, dibasic sodium phosphate
(heptahydrate) 0.730 g, and monobasic sodium phosphate
(monohydrate) 0.311 g, in Water for Injection, pH 6.7-7.4
Clinical Pharmacology
A gradual depletion of red blood cell adenosine
triphosphate (ATP) and 2,3 diphosphoglycerate (2,3-DPG)
occurs with storage of RBC at 1-6°C.1 The level of 2,3-DPG
in RBC stored for greater than 14 days is less than 10% of
normal.1,2,11,16,17 Rejuvenation of RBC with rejuvesol red
blood cell processing solution increases the levels of ATP
and 2,3-DPG.1,2,3,4,5,12,16,17,18,19,20,21,23
An in vitro loss of red blood cells occurs with the
preservation and processing of RBC. Thus, the effectiveness
of a transfusion is influenced by both the total number of
red blood cells transfused and the number of those cells
which remain in circulation. Therefore, the “dose” of a
transfusion is defined as the percentage of pre-transfusion
recovered red blood cells multiplied by the 24 hour posttransfusion survival value.
Rejuvenation is accomplished by incubating the contents
of one 50 mL vial of rejuvesol Solution with one unit of RBC
(prepared from up to 550 mL of whole blood) for sixty (60)
minutes at 37°C. Citra Labs recommends that the entire
50 mL of rejuvesol Solution be added to a “smaller than
normal” RBC as long as the pre-rejuvenation net packed
cell weight is greater than 110 grams.1,8
Indication and Usage
rejuvesol Solution is intended only to be used as an in
vitro processing solution for the rejuvenation of a unit of
RBC. RBC may be rejuvenated after 14 days of storage in
CPD (non-leukocyte reduced), CPDA-1, (non-leukocyte
6
reduced) or CPD/ADSOL® (CPD/AS-1 leukocyte reduced).
The final concentration of ATP and 2,3-DPG achieved after
rejuvenation will vary depending on the number of days of
liquid storage at 1-6°C prior to rejuvenation.
NOTE: For simplicity, RBC stored in CPD (non-leukocyte
reduced), CPDA-1 (non-leukocyte reduced), or CPD/ADSOL®
(CPD/AS-1 leukocyte reduced) are referred to hereafter as
CPD, CPDA-1, and CPD/AS-1, respectively.
It is at the discretion of the Medical Director when
rejuvenation of a RBC should take place. Citra Labs, LLC,
recommends that rejuvenation of RBC be performed after
14 days or longer of liquid storage.
RBC (CPD, CPDA-1, and CPD/AS-1) rejuvenated before 6
days of storage may achieve 2,3-DPG levels in excess of 2
times normal and ATP levels in excess of 1.5 times normal.5,6
(See Warning and Contraindications).
Rejuvenation of CPD or CPDA-1 RBC
RBC which have been collected and stored in CPD or
CPDA-1 anticoagulant may be rejuvenated up to three days
after the expiration date of the RBC, as long as storage at
1-6°C is not interrupted.3,4 After rejuvenation, RBC (CPD
and CPDA-1) must be either washed and stored at 1-6°C for
up to 24 hours prior to transfusion or glycerolized and
frozen at –80°C (below –65°C). Red Blood Cells (Frozen
Rejuvenated) which were collected and stored in CPD or
CPDA-1 may be stored frozen up to 10 years.9
When RBC are rejuvenated after maximum liquid storage,
i.e., CPD RBC at 24 days or CPDA-1 RBC at 38 days, the
concentrations of 2,3-DPG and ATP increase typically to
above normal.1,3-5,6
CAUTION: RBC collected in CPD or CPDA-1 cannot be
leukocyte reduced prior to rejuvenation.
Rejuvenation of CPD/AS-1 RBC
rejuvesol Solution has not been approved for the
rejuvenation of RBC stored in any additive systems
other than AS-1. RBC stored in CPD/AS-1 at 1-6°C may be
rejuvenated up to, but not exceeding, 42 days of storage
as long as storage at 1-6°C is not interrupted. Rejuvenated
CPD/AS-1 RBC must be glycerolized and frozen. Red Blood
Cells, Frozen Rejuvenated which were collected and
stored in CPD/AS-1 may be stored for up to 3 years. Unlike
rejuvenated CPD and CPDA-1 RBC, rejuvenated CPD/AS-1
RBC have not been approved to be immediately washed
and transfused.
When CPD/AS-1 RBC are rejuvenated at 42 days of liquid
storage, frozen, deglycerolized, and stored for 24 hours,
the concentration of 2,3-DPG and ATP increases to above
normal. In a limited study, the average 24 hour posttransfusion survival value of these cells was statistically
higher than the reported12 survival value of CPD/AS-1 red
blood cell concentrates which are stored for 42 days prior
to transfusion. The “dose” may be equivalent for a CPD/
AS-1 RBC whether the unit is stored for 42 days prior to
transfusion or stored for 42 days, rejuvenated, frozen,
deglycerolized, and stored for 24 hours prior to transfusion.
Warning and Contraindications
rejuvesol Solution is intended only for the extracorporeal
rejuvenation of a RBC. It should not be directly administered
to humans.
rejuvesol Solution must not be added to whole blood
because the additional plasma may reduce the effectiveness
of the rejuvenation process. Immediately after rejuvenation,
RBC must either be washed via an approved protocol
prior to transfusion or glycerolized and frozen. RBC which
have been rejuvenated, glycerolized, and frozen must be
deglycerolized via an approved protocol prior to transfusion.
RBC rejuvenated before 6 days of storage may achieve
2,3-DPG levels in excess of 2 times normal and ATP levels
in excess of 1.5 times normal.5,6 In patients with reduced
arterial blood p02 of less than 40 torr, the use of RBC
rejuvenated before 6 days of storage are contraindicated
because their high 2,3-DPG levels and low oxygen affinity
may impair proper oxygenation of the red blood cells in
the lung.7
Rejuvenated RBC are further processed prior to transfusion
to remove the unused portion of rejuvesol Solution,
by-products of the rejuvenation process, and any other
potential storage related impurities in rejuvesol Solution.
Based on the concentration of the residual inosine in
rejuvenated, deglycerolized RBC, the average washout
of inosine was calculated to be 99.8%. A literature search
for potential toxicity associated with the ingredients
that comprise rejuvesol Solution, including potential
metabolites, was conducted.22 This report concludes that
no theoretical contraindications would be associated with
the transfusion of a single unit of unwashed, rejuvenated
RBC that would contain amounts of pyruvate, inosine,
adenine, phosphate, hypoxanthine, uric acid, and lactate
that exceed reference values (excluding lactate) as these
substances are naturally metabolized and/or are excreted.22
The maximum number of properly processed rejuvenated
RBC that can be transfused to a single recipient over their
entire lifetime has not been determined.
Precautions
• Aseptic technique must be maintained at all times.
• Do not use unless solution is clear/colorless and seal is
intact. Product that exhibits a slight yellow color should
not be used. Product instability has been observed
after continuous exposure at high temperature (after
6 months at 40°C and after 9 months at >30°C).
• This product contains no bacteriostatic or antimicrobial
agents and is intended for single use only.
• Rx Only - Federal (USA) law prohibits dispensing without
prescription.
Storage
It is recommended that the product be stored at 15–25°C
(59–77°F). Protect from freezing. Exposure to temperatures
near or below freezing may produce a white precipitate
in the solution; this precipitate will dissolve upon brief
incubation at room temperature. Alternatively, the product
may be warmed at 37°C for up to one hour in a dry air
incubator to dissolve the precipitate.
How Supplied
PN 7012: 50 mL vial; 12 vials per case
To Order
Contact Citra Labs Customer Service
e: [email protected]
p: 800.299.3411 (toll free)
p: 781.848.2174 (MA)
f: 781.848.6781
You are encouraged to report negative side effects
of prescription drugs to the FDA. Visit MedWatch4
or call 1-800-FDA-1088.
7
Sample Standard Operating Procedures (SOP)
8
Sample Standard Operating Procedures (SOP)
rejuvesol red blood cell processing solution
Rejuvenation of RBC Prior to Immediate Use
Refer to product labeling for detailed instructions for use
1.0Introduction
1.1 rejuvesol red blood cell processing solution (rejuvesol Solution) is intended to be used as an in vitro
processing solution for the rejuvenation of a unit of red blood cells (RBC). rejuvesol Solution restores
2,3-diphosphoglycerate (2,3-DPG) and adenosine triphosphate (ATP) to fresh levels in treated RBCs. The final
concentration of ATP and 2,3-DPG achieved after rejuvenation will vary depending on number of days of
liquid storage at 1-6°C prior to rejuvenation.
2.0Purpose
2.1 This document outlines steps necessary for using rejuvesol Solution to rejuvenate a unit of RBC prior
to immediate use.
3.0Scope
3.1 This procedure may be applied to RBC for rejuvenation prior to immediate use. Immediate use is defined
as within the subsequent 24 hours and not cryopreserved.
4.0 Materials and Equipment (As suggested or equivalent)
NOTE: Refer to Appendix A for Materials and Equipment Checklist
4.1 An FDA cleared cell washer/washing system
4.2 Temperature-controlled (circulating) water bath
4.3 Integral tubing sealer
4.4 Sterile alcohol swabs (70%)
4.5 One sterile vial (50 mL) of rejuvesol Solution (Citra PN 7012)
4.6 Y-type Rejuvenation Set (Citra PN 7212) or equivalent
4.7 Two watertight plastic overwrap bags and weights
4.8 Waterproof tape
4.9 Overwrap bag impulse sealer (optional)
4.10 Sterile Docking Device (SCD)
5.0Procedure
5.1 Combine rejuvesol Solution with RBC
5.1.1 Remove flip-off protective cap from the rejuvesol Solution vial and clean exposed rubber stopper
surface with alcohol swab.
5.1.2 Close all slide clamps of Y-type Rejuvenation Set (Citra PN 7212). Heat seal integral tubing between
transfer bag and Y connector, detach and discard empty transfer bag.
9
Sample Standard Operating Procedures (SOP)
5.1.3
Aseptically insert vented spike of Y-type Rejuvenation Set into stopper of rejuvesol Solution.
5.1.4 Sterile connect tubing of Y-type Rejuvenation Set to primary collection bag. Alternately, aseptically
insert spike of Y-type Rejuvenation Set into one port of primary collection bag.
5.1.5
Elevate rejuvesol Solution vial above primary collection bag.
5.1.6
Squeeze drip chamber to prime and open slide clamp of Y-type Rejuvenation Set.
5.1.7
Allow entire contents of rejuvesol Solution vial to flow into primary collection bag while gently agitating
mixture.
5.1.8
After all rejuvesol Solution has been transferred, close slide clamp and heat seal tubing above primary
collection bag.
5.1.9
Disconnect at heat seal; discard used tubing and empty rejuvesol Solution vial.
5.1.10 Proceed immediately to Section 5.2.
5.2 Incubate RBC/rejuvesol Solution mixture for 60 minutes at 37°C.1,8,10,12
NOTE: Incubation timing is initiated when RBC/rejuvesol Solution mixture is introduced into the water bath. Actual
temperature of RBC/rejuvesol Solution mixture does not reach 37°C (the final temperature is usually 29-31°C).
5.2.1 Place primary collection bag containing RBC/rejuvesol Solution mixture into a plastic overwrap bag
and remove air.
5.2.2 Seal plastic overwrap bag.
5.2.3 Place sealed overwrapped unit inside second overwrap bag containing weights (to keep the unit
submerged during incubation); remove air and seal.
5.2.4 Place overwrapped unit in water bath and secure.
5.2.5 Incubate unit at 37°C for 60 minutes.
5.2.6 Remove unit, blot dry outer overwrap bag and carefully remove overwraps from RBC/rejuvesol Solution
mixture.
NOTE: Use caution to ensure primary collection bag and mixture are not contaminated with any water.
5.3 Process red blood cell/rejuvesol Solution mixture after incubation.3,10
Use an approved cell washing system and standard operating procedures for that system to wash RBC/
rejuvesol Solution mixture. 3 The rejuvenated, washed RBC may be stored at 1-6°C for up to 24 hours prior to
transfusion. 3,9,10
NOTE: No more than four (4) hours should elapse between the time the unit is removed and returned to the
1-6°C storage environment.10
6.0 Labeling and Documentation
6.1 Ensure appropriate documentation of rejuvenation incubation start time to calculate expiration time.
Document product modification per facility protocols.
6.2 Ensure rejuvenated unit is properly labeled according to current guidelines and facility protocols.
10
Rejuvenation of RBCs: Prior to Immediate Use
rejuvesol Red Blood Cell
Processing Solution Bottle
Primary Collection Container
of RBCs in CPD or CPDA-1
Slide Clamp
(Open & Closed)
Y-Type Rejuvenation Set
Clamp A
Clamp B
Clamp A
Clamp B
Clamp B
Clamp A
All clamps are closed.
Clamp A
Heat seal the integral tubing.
Detach and discard the empty transfer bag.
Clamp A
Clamp B
28 in
Clamp B
Bottle & RBC bag are
connected to tubing set.
Clamp A
Clamp B
Mixing
Squeeze drip chamber to prime.
Bottle is raised 28 in. above RBCs.
Clamp B is opened and rejuvesol Solution
is transferred. Gently agitate mixture.
Close slide clamp. Heat seal
the tubing three times.
Cut the middle heat seal.
Remaining materials are double
over-wrapped in plastic.
Over-wrapped materials are
put in circulating water bath
37° C for 60 minutes.
Wash RBCs immediately
per operating procedure.
11
Sample Standard Operating Procedures (SOP)
rejuvesol red blood cell processing solution
Rejuvenation of RBC Prior to Cryopreservation
Refer to product labeling for detailed instructions for use
1.0Introduction
1.1 rejuvesol red blood cell processing solution (rejuvesol Solution) is intended only to be used as an in vitro
processing solution for the rejuvenation of a unit of red blood cell (RBC). rejuvesol Solution restores
2,3-diphosphoglycerate (2,3-DPG) and adenosine triphosphate (ATP) to fresh levels in treated RBCs. The final
concentration of ATP and 2,3-DPG achieved after rejuvenation will vary depending on the number of days of
liquid storage at 1-6 °C prior to rejuvenation.
2.0Purpose
2.1 This document outlines the procedure necessary for using rejuvesol Solution to rejuvenate a unit of RBC prior
to cryopreservation.
3.0Scope
3.1 This procedure is to be applied to any RBC unit intended for rejuvenation prior to cryopreservation.
4.0 Materials and Equipment (As suggested or equivalent)
NOTE: Refer to Appendix A for Materials and Equipment Checklist
4.1 Temperature-controlled (circulating) water bath
4.2 Integral tubing sealer
4.3 Sterile alcohol swabs (70%)
4.4 One sterile vial (50 mL) of rejuvesol Solution (Citra PN 7012)
4.5 Y-type Rejuvenation Set (Citra PN 7212)
4.6 Two watertight plastic overwrap bags and weights
4.7 Waterproof tape
4.8 Overwrap bag impulse sealer (optional)
4.9 Sterile Docking Device (SCD)
5.0Procedure
5.1 Combine rejuvesol Solution with the RBC
5.1.1 Remove flip-off protective cap from the rejuvesol Solution vial and clean exposed rubber stopper
surface with alcohol swab.
12
5.1.2
Close all slide clamps of Y-type Rejuvenation Set (Citra PN 7212).
5.1.3
Aseptically insert vented spike of the Y-type Rejuvenation Set into the stopper of rejuvesol Solution.
5.1.4 Sterile connect tubing of Y-type Rejuvenation Set to primary collection bag. Alternately, aseptically
insert spike of the Y-type Rejuvenation Set into one port of primary collection bag.
5.1.5
Elevate rejuvesol Solution vial above primary collection bag.
5.1.6
Squeeze drip chamber to prime and open slide clamp of the Y-type Rejuvenation Set.
5.1.7
Allow entire contents of rejuvesol Solution vial to flow into primary bag while gently agitating mixture.
5.1.8 After all rejuvesol Solution has been transferred, close slide clamp and heat seal tubing between
rejuvesol Solution vial and 3-way connector of Y-type Set.
5.1.9
Disconnect at heat seal and discard empty rejuvesol Solution vial.
5.1.10 Proceed immediately to Section 5.2.
5.2 Incubate RBC/rejuvesol Solution mixture for 60 minutes at 37°C.1,8,10,12
NOTE: Incubation timing is initiated when RBC/rejuvesol Solution mixture is introduced into the water bath. Actual
temperature of RBC/rejuvesol Solution mixture does not reach 37°C (the final temperature is usually 29-31°C).
5.2.1
Place primary collection bag containing RBC/rejuvesol Solution mixture into a plastic overwrap bag and
remove air.
5.2.2 Seal plastic overwrap bag.
5.2.3 Place sealed overwrapped unit inside second overwrap bag containing weights (to keep the unit
submerged during incubation); remove air and seal.
5.2.4 Place overwrapped unit in water bath and secure.
5.2.5 Incubate unit at 37°C for 60 minutes.
5.2.6 Remove unit, blot dry outer overwrap bag and carefully remove overwraps from RBC/rejuvesol Solution
mixture.
NOTE: Use caution to ensure primary collection bag and mixture are not contaminated with any water.
5.3 Process RBC/rejuvesol Solution mixture after incubation.1,9,10
Complete the glycerolization procedure per Standard Operating Procedure.1,9,10
NOTES:
i. After incubation, the red blood cell/rejuvesol Solution mixture may need to be concentrated prior to the
addition of glycerol solution to insure proper glycerolization.1,9,11,13 The Y-type Rejuvenation Set contains a
transfer bag that may be utilized for this purpose.
ii. No more than four (4) hours should elapse between the time the unit is removed and returned to the 1-6°C
storage environment.10
6.0 Labeling and Documentation
6.1 Document product modification per facility protocols.
6.2 Ensure rejuvenated unit is properly labeled according to current guidelines and facility protocols.
13
Sample Standard Operating Procedures (SOP)
Rejuvenation of RBCs: Prior to Cryopreservation
rejuvesol Red Blood Cell
Processing Solution Bottle
Primary Collection Container of
RBCs in CPD, CPDA-1 or CPD/AS-1
Clamp A
Slide Clamp
(Open & Closed)
Clamp A
Clamp B
All clamps are closed.
Clamp A
Clamp B
Bottle & RBC bag are
connected to tubing set.
Clamp A
Clamp B
Squeeze drip chamber to prime.
Bottle is raised 28 in. above RBCs.
Clamp A
Clamp B
14
Y-Type Rejuvenation Set
Clamp B
Clamp B is opened and rejuvesol
Solution is transferred. Gently agitate
mixture during transfer.
Close the slide clamp. Heat seal the tubing
three times. Cut the middle heat seal.
Over-wrapped materials are
put in circulating water bath
37°C for 60 minutes.
Glycerolize and freeze per standard
operating procedure. If required,
centrifuge rejuvenated RBC.
Remaining materials are double
over-wrapped in plastic.
Training & Competency Assessment
15
Training & Competency Assessment
Objectives of Training Session
Training Checklist
NOTE: Refer to Appendix B—Training Presentation for
user training materials.
By checking, the trainee documents completion of the
indicated steps:
Successful trainees will be able to achieve the following,
as evidenced by demonstrated proficiency using rejuvesol
Solution to rejuvenate a unit of red blood cells.
Has read and understood:
• Identify appropriate unit and supplies for rejuvenation.
• Properly use Y-type Rejuvenation Set (or equivalent)
for addition of rejuvesol Solution to RBC.
• Incubate unit at appropriate time and temperature.
rejuvesol red blood cell process solution
Instructions for Use
Facility SOP for use of rejuvesol Solution
Has successfully demonstrated:
Ability to select appropriate unit for rejuvenation
Proper inspection of rejuvesol Solution and disposable
set prior to use
Understanding of use of Y-type Rejuvenation Set
Proper incubation time and temperature
for rejuvenation
Trainee’s Printed Name
Date
Trainee’s Signature
Trainer’s Printed Name
Trainer’s Signature
16
Date
Quiz
Trainee’s Name
Date
Circle the letter of the correct response.
1. rejuvesol red blood cell processing solution
(rejuvesol Solution) may be used to improve oxygen
delivery capacity of transfused red blood cells.
7. Rejuvenated red blood cells are to be washed with
prior to infusion.
a. 0.9% Saline (NaCl)/0.2% Dextrose
a.True
b. 0.5% Dextrose
b.False
c. Sterile Water for Injection
d. Lactated Ringers
2. rejuvesol Solution is supplied in 50 mL glass vials,
each vial treats one unit of red blood cells.
a.True
b.False
8. Rejuvenated red blood cells (for immediate use)
should be transfused within:
a. 24 hours
b. 42 days
3. rejuvesol Solution contains glycerol.
a.True
b.False
9. rejuvesol Solution is washed off the treated red
blood cells prior to infusion. This wash process:
a. Removes residual rejuvesol solution
4. 2,3-DPG levels decline rapidly within the first
2 weeks, while ATP levels decline steadily during
storage of donated red blood cells.
a.True
b. Removes by-products of rejuvenation
c. Removes plasma proteins and other unwanted
analytes
d. All of the above
b.False
5. Rejuvenated, frozen CPD/AS-1 red blood cells
are approved for up to 3 years of shelf life.
10. rejuvesol Solution must incubate with the red blood
cells at
degrees for
minutes.
a. 37°C and 30 minutes
a.True
b. 24°C and 30 minutes
b.False
c. 24°C and 60 minutes
d. 37°C and 60 minutes
6. rejuvesol Solution contains the following ingredients:
a. Phosphate, Adenine, Glycerol, Inosine
b. Phosphate, Inosine, Pyruvate, Adenine
c. Pyruvate, Mannitol, Adenine, Glucose
d. Pyruvate, Inosine, Glucose, Adenine
Quiz answers on Page 30
17
FDA Approval Statement
18
FDA Approval Statement
rejuvesol red blood cell processing solution, Part Number: 7012
NDA Number
BN950522
Trade name
rejuvesol Solution
Original Applicant
Cytosol Laboratories, Inc.
55 Messina Drive
Braintree, MA 02184 US
Current Owner
Citra Labs, LLC, a Biomet Biologics Company
55 Messina Drive
Braintree, MA 02184 US
Type
New Drug Application (CBER)
Y-Type Rejuvenation Set, Part Number: 7212
510(k) Number
BK950060
Trade name
Y-Type Rejuvenation Set
Original Applicant
Cytosol Laboratories, Inc.
55 Messina Drive
Braintree, MA 02184 US
Current Owner
Citra Labs, LLC, a Biomet Biologics Company
55 Messina Drive
Braintree, MA 02184 US
Type
510(k) Traditional
19
Process Validation & Control
20
Process Validation & Control
Process Validation
Process Control
As is presented elsewhere within this Handbook, Citra
Labs has met the US FDA requirements to obtain approval
to market rejuvesol red blood processing solution. Data
gathered during multicenter trials included pre and postrejuvenation 2,3-DPG and ATP analysis.12 Studies confirmed
rejuvesol Solution consistently performed as expected
when handled according to manufacturer’s instructions.12
As with most blood product manufacturing, AABB
Standards require ongoing process control as is found
below:
The objective of process validation for rejuvesol Solution
is to generate evidence ensuring each RBC unit, when
rejuvenated and processed according to SOP, will
consistently yield expected post-rejuvenation results.24
The rejuvesol Solution validation process is subjective—
organizations may validate the rejuvenation process
multiple ways. Sample size may be limited to a small
quantity for the purposes of challenging draft standard
operating procedures. Validation should, at a minimum,
include a walk-through of draft standard operating
procedures for rejuvenation prior to immediate transfusion
and/or cryopreservation used in tandem with a previously
validated washing and/or deglycerolizing process.
Validation should also confirm appropriate processes are in
place for properly labeling rejuvenated products.
Rejuvenated Deglycerolized Red Blood Cells25:
1. Adequate removal of cryoprotective agents
2. Minimal free hemoglobin in supernatant solution
3. Mean recovery of ≥80% of the preglycerolized red cells
Rejuvenated Washed Red Blood Cells25:
1. Use of “Method known to ensure that the red cells are
washed with a volume of compatible solution that will
remove almost all of the plasma”, i.e., ensure standard
washed process functions as expected by performing
any routine QC prescribed by respective facility.
The following tests may be considered for qualitative/
quantitative post-rejuvenation data analysis:
Intent: Ensure adequate post-rejuvenation wash process:
• Total Protein analysis
• Specific Gravity
(dipstick or chemistry)
by refractometer
(or equivalent)
•Osmolality
Intent: Ensure adequate rejuvenation process:
•p50
• 2,3-DPG levels
• ATP levels
21
ISBT Labeling
22
ISBT Labeling
Blood Product Labeling
As with all blood and blood components, please label in compliance
with ISBT 128 Nomenclature.
Washed, Deglycerolized, or Rejuvenated Red Blood Cells*
Neither the anticoagulant nor the nominal collection volume needs
to appear on the label. The actual volume shall appear on the label.
Proper Name**
NOTE: Refer to current IFU for approved indications for use.
Modifier
Component Class
Proper Name
Frozen Rejuvenated
Red Blood Cells
Frozen Rejuvenated
Red Blood Cells
Deglycerolized Rejuvenated
Red Blood Cells
Deglycerolized Rejuvenated
Red Blood Cells
Rejuvenated
Red Blood Cells
Rejuvenated
Red Blood Cells
Frozen Rejuvenated Apheresis
Red Blood Cells
Frozen Rejuvenated Apheresis
Red Blood Cells
Deglycerolized Rejuvenated Apheresis
Red Blood Cells
Deglycerolized Rejuvenated Apheresis
Red Blood Cells
Rejuvenated Apheresis
Red Blood Cells
Rejuvenated Apheresis
Red Blood Cells
Product Codes***
Should be identified using the ICCBBA Product Description Code
Database or the Product Description Code Lookup Program
found in the Members Only section of the ICCBBA website,
ICCBBA.org.
* ICCBBA US Consensus Standard, Version 3.0.0, March 2013 Section 7.8.5
** ICCBBA US Consensus Standard, Version 3.0.0, March 2013, Section 6.2
*** ICCBBA US Consensus Standard, Version 3.0.0, March 2013, Sections 4.3 and 8.2
23
Frequently Asked Questions
24
Frequently Asked Questions
Product Questions
rejuvesol red blood cell processing solution
1. What is rejuvesol Solution?
It is a sterile, non-pyrogenic solution of pyruvate,
inosine, adenine, and phosphate in water for injection
and intended only for use in the extracorporeal
rejuvenation of a unit of red blood cell (RBC)
concentrate.26
2. How does rejuvesol Solution work?
rejuvesol Solution restores 2,3-DPG and ATP of liquid
stored RBCs to “fresh” levels by conversion of the
pyruvate, Inosine, adenine, and/or phosphate through
natural enzymatic pathways within the RBC.26
3. When should rejuvesol Solution be used?
It is intended for rejuvenation of RBCs stored as CPD,
CPDA-1 or CPD/AS-1 prior to cryopreservation. In
addition, it is intended for rejuvenation of RBC (CPD or
CPDA-1) that are to be washed prior to immediate use.26
4. How is a unit of red blood cells (RBCs) rejuvenated?
rejuvesol Solution is added to the unit of RBC and the
mixture is incubated at 37°C for 60 minutes. Refer to
the IFU for more detailed instructions.
5. What is the Y-Type Rejuvenation Set?
8. Does rejuvesol Solution have to be refrigerated
after opening?
The entire contents of the 50 mL vial of rejuvesol
Solution is considered a single dose and should be
used upon opening.26 Additionally, rejuvesol Solution
is to be stored between 15oC and 25oC.
9. Can a unit of rejuvenated RBCs be transfused
without further processing?
The rejuvenated RBCs must be washed (if for immediate
transfusion) or cryopreserved (for later use). Refer to
the IFU for more detailed instructions.26
10.Can RBCs stored in additive solution AS-1 be
rejuvenated after Day 42 of liquid storage?
RBCs stored in AS-1 can be rejuvenated up to day 42.26
11. Can RBCs be rejuvenated if it has been stored in
AS-3 or AS-5?
No, rejuvesol Solution is currently indicated for
rejuvenation of RBCs stored in AS-1.26
12. When RBCs are stored in additive solution AS-1 and
rejuvenated, can they be washed for immediate
transfusion?
It is a tubing set to assist in the transfer of rejuvesol
Solution into the RBCs unit. Its Part Number is PN7212.
Refer to current Instructions for Use for detailed
indications for use.
6. What equipment can be used to incubate the RBC /
rejuvesol Solution mixture?
13. How can I order rejuvesol red blood cell processing
solution and the Y-Type Rejuvenation Set?
Currently, rejuvenation with rejuvesol Solution
is approved using a circulating water bath (or
equivalent).26
Contact Citra Customer Service at 1-800-299-3411 or
via email at [email protected]. You may also fax
purchase orders directly to 781.848.6781.
7. Can a 50 mL vial of rejuvesol Solution be used to
treat multiple units of RBCs?
14. What is the expiration date for rejuvesol red blood
cell processing solution?
A 50 mL vial of rejuvesol Solution is approved as a
single dose to rejuvenate a unit of RBCs.26
Refer to vial labeling (14 months from the date of
manufacture).
25
Frequently Asked Questions
Product Questions (cont.)
Pricing / Returns
15.What is the expiration date for the Y-Type
Rejuvenation Set?
1. How much does rejuvesol Solution cost?
Refer to Y-Type Rejuvenation Set labeling (3 years from
date of manufacture).
16. What are rejuvesol Solution contraindications?
rejuvesol Solution is intended for extracorporeal
rejuvenation of RBCs stored in CPD, CPDA-1 or CPD/
ADSOL (CPD/AS-1 leukocyte reduced). It should not be
directly administered to humans. Refer to the IFU for
more detailed contraindications.26
17. What is the rejuvesol Solution pregnancy category?
Safety and efficacy studies of rejuvesol Solution treated
RBCs, specifically during a pregnancy, have not been
performed. The use of rejuvenated RBCs is a clinical
judgment of the prescribing physician.
18. Are rejuvenated RBCs better than fresh RBCs?
Rejuvenation of RBCs with rejuvesol Solution restores
2,3-DPG and ATP of liquid stored RBCs to “fresh”
levels.26
19.Is this the same rejuvesol Solution I previously
ordered from Cytosol Laboratories (enCyte
Systems, Inc.)?
Yes, the product and rejuvenation process remain the
same.
20. Does rejuvesol Solution contain latex?
No, rejuvesol Solution is latex free.
21.
What is the acceptable tolerance for the
temperature of the 37°C water bath used to
incubate the RBCs / rejuvesol Solution mixture?
The water bath temperature control should be set at
37°C and capable of holding the temperature at ±1°C.
26
rejuvesol Solution (PN7012) is distributed as a 12 unit
pack. Pricing is available via Citra Labs Customer
Service at 1-800-299-3411.
2. What is the return policy for rejuvesol Solution?
Contact customer service at 1-800-299-3411 for
returned goods authorization (RGA) Guidance.
Regulatory
1. What type of clearance does rejuvesol Solution
have in the US?
The Federal Drug Administration approved rejuvesol
Solution on February 27, 1997. It is approved for use
as a drug. It currently falls under jurisdiction of Center
of Biologics Evaluation and Research (CBER) which
regulates biological products for human use. For
additional details, refer to FDA Approval Statement in
this handbook.
2.What type of clearance does
Rejuvenation Set have in the US?
the
Y-Type
The Y-Type Rejuvenation Set is cleared under a 510k.
For additional details, refer to FDA Approval Statement
in this handbook.
3. Are rejuvesol Solution and the Y-Type Rejuvenation
Set available outside of the United States?
rejuvesol Solution and the Y-Type Rejuvenation Set are
only approved for use in the United States.
4. Can I purchase rejuvesol Solution and the Y-Type
Rejuvenation Set for shipment to (country X)?
No, rejuvesol Solution and the Y-Type Rejuvenation Set
are only approved for use in the United States.
Quality
1. Who should I notify if I have a product experience
or complaint to report?
Please promptly report any experiences or concerns to
Citra Labs Customer Service at 1-800-299-3411 or via
email at [email protected].
Company
1. Where is rejuvesol Solution manufactured?
rejuvesol Solution is manufactured for Citra Labs by
Grand River Aseptic Manufacturing, Inc., located in
Grand Rapids, MI.
2. Is Citra Labs part of Biomet?
Yes, Citra Labs, LLC is a wholly owned subsidiary of
Biomet, Inc. and Biomet Biologics, LLC.
3. What happened to Cytosol Laboratories and
enCyte Systems?
Biomet, Inc. and Biomet Biologics, LLC purchased
certain assets of Cytosol Laboratories, Inc., Citra
Anticoagulants, Inc., and enCyte Systems, Inc., and
transferred and assigned those assets to Citra Labs,
LLC, a wholly owned subsidiary of Biomet, Inc. and
Biomet Biologics, LLC.
Samples
1. Is it possible to obtain samples of rejuvesol Solution
and the Y-Type rejuvenation set?
Yes, visit rejuvesol.com to request samples and view
the sample policy.
27
Appendices
Appendix A: Materials and Equipment Checklist
Materials/Equipment (As suggested or equivalent)
An FDA cleared cell washer/washing system*
Temperature-controlled (circulating) water bath
Integral tubing sealer
Sterile alcohol swabs (70%)
One sterile vial (50 mL) of rejuvesol Solution (Citra PN 7012)
Y-type Rejuvenation Set (Citra PN 7212)
Two watertight plastic overwrap bags and weights
Waterproof tape
Overwrap bag impulse sealer (optional)
Sterile Docking Device (SCD)
*Required for immediate use only
28
Appendix B: Training Presentation
Refer to rejuvesol.com for on-line training presentation/video.
Questions or comments? Please contact us:
Citra Labs Customer Service
p:1-800-299-3411
e:[email protected]
Product Quiz Answer Key
1.A
6.B
2.A
7.A
3.B
8.A
4.A
9.D
5.A
10.D
29
Notes
References
1.Valeri CR, CG Zaroulis, Rejuvenation and Freezing of Outdated Stored
Human Red Blood Cells; NEJMED 1972;287:1307-1313.
2. Valeri CR. Unpublished Data.
3. Valeri CR, AD Gray, GP Cassidy, et al.; The 24-hour posttransfusion survival,
oxygen transport function, and residual hemolysis of human outdated
rejuvenated red cell concentrates after washing and storage at 4 °C for 24
to 72 hours. Transfusion 1984; 24:323-6.
4. Valeri CR, CG Zaroulis, JJ Vecchione, et al.; Therapeutic effectiveness and
safety of outdated human red blood cells rejuvenated to restore oxygen
transport function to normal, frozen for 3 to 4 years at –80 °C, washed,
and stored at 4 °C for 24 hours prior to rapid infusion. Transfusion 1980; 20:
159-70.
5.Valeri, CR, DA Valeri, JJ Vecchione, and CP Emerson; Biochemical
modification and freeze preservation of red blood cells, Critical Care Med.
7 (9):439-477,1979.
6. Valeri CR; Status report on rejuvenation and freezing of red blood cells.
Plasma Therapy 2 (3): 155-170, 1981.
13. Gelderman MP and Vostal JG; Rejuvenation Improves Roller Pump-Induced
Stress resistance of Fresh and Stored Red Blood Cells. Transfusion 51:10961104, 2011.
14.Meyer EK, et al; Rejuvenation Capacity of Red Blood Cells in Additive
Solutions Over Long-Term Storage. Transfusion, 51(7):1574-1579, 2011.
15. Koshkaryev A, et al; Rejuvenation Treatment of Stored Red Blood Cells
Reverses Storage-Induced Adhesion to Vascular Endothelial Cells.
Transfusion, 49:2136-2143, 2009.
16. Dennis RC, et al; Transfusion of 2,3-DPG-Enriched Red Blood Cells to
Improve Cardiac Function. Ann. Thor. Surg., 26:16-17, 1978.
17. Valeri CR, et al; Improved Oxygen Delivery to the Myocardium During
Hypothermia by Perfusion with 2,3-DPG Enriched Red Blood Cells. Ann.
Thorac. Surg., 30(6): 527-535, 1980.
18. Valeri CR, et al; Human Red Blood Cells with Normal or Improved Oxygen
Transport Function Prepared and Frozen in the Primary Polyvinyl Chloride
Plastic Blood Collection Container. Transfusion and Immunohaematology,
22:467-486, 1979.
7. Boston University School of Medicine/Naval Blood Research Laboratory,
Boston, MA Standard Operating Procedure—Red Blood Cells Collected
in the CPDA-1 800 mL Primary PVC Plastic Collection Bag System and
Stored for 3 to 35 Days (Indated-Rejuvenated) or for 36 to 38 Days
(Outdated-Rejuvenated), Biochemically Modified with PIPA Solution Prior
to Glycerolization in the Primary 800 mL Bag with the Special Adaptor Port
Using 40% W/V Glycerol and Storage at –80 °C, Washed in the Haemonetics
Blood Processor 115, and Stored at 4 °C for 24 Hours Prior to Transfusion
(Revised 5/91).
19.Ragno G and Valeri, CR, Salvaging of Liquid-Preserved O-Positive and
O-Negative Red Blood Cells by Rejuvenation and Freezing. Transfus. Apher.
Sci., 35(2): 137-143, 2006.
8. Valeri CR: Simplification of the methods for adding and removing glycerol
during freeze-preservation of human red blood cells with the high or low
glycerol methods: Biochemical modification prior to freezing. Transfusion
15(3):195-218, 1975.
22. Loeb, WF, V.M.D, Ph.D; A Literature Review to Investigate the Feasibility of
Modifying the Current Protocol for Use and Developing New Applications.
unpublished communication, 19 Oct 2000.
9. AABB Standards for Blood Banks and Transfusion Services, 27th Edition.
10. American Association of Blood Banks Technical Manual, pages 946-953,
17th Edition, 2011.
20. Valeri CR, et al; Automation of the Glycerolization of Red Blood Cells
with the High-Separation Bowl in the Haemonetics ACP 215 Instrument.
Transfusion 45: 1621-1627, 2005
21. Lockwood WB, et al; Effects of Rejuvenation and Frozen Storage on 42-DayOld AS-3 RBCs. Transfusion 43(11): 1527-153, 2003.
23. Valeri CR, et al; The Survival, Function, and Hemolysis of Human RBCs
Stored at 4 °C in Additive Solution (AS-1, AS-3, and AS-5) for 42 Days and
then Biochemically Modified, Frozen, Thawed, Washed, and Stored at 4°C in
Sodium Chloride and Glucose for 24 Hours. Transfusion 40: 1341-1345, 2000.
11. Valeri CR, LE Pivacek, M Palter, RC Dennis, N Yeston, CP Emerson, and MD
Altschule; A clinical experience with ADSOL® preserved erythrocytes.
Surgery, Gynecology, and Obstetrics 166:33-46, 1988.
24. “Guidance for Industry-Process Validation: General Principals and Practices”
FDA, Jan. 2011.
12. Szymanski IO, Teno RA, Lockwood WB, Hudgens, R, and Johnson, GS; Effect
of rejuvenation and frozen storage on 42-day-old AS-1 RBCs. Transfusion 41:
550-555, 2001.
26. Instructions for Use (IFU); rejuvesol red blood cell processing solution.
25. AABB Standards for Blood Banks and Transfusion Services, 29 th Edition, p. 26.
All content herein are the property of Biomet, Inc. or its subsidiaries unless
otherwise indicated. This material is intended for healthcare professionals and
must not be redistributed, duplicated, or disclosed without the express written
consent of Biomet. For complete product information, see the package insert and
www.rejuvesol.com. Biomet does not practice medicine. The treating surgeon is
responsible for determining the appropriate treatment, technique and producs
for each individual patient.
Legal Manufacturer
Biomet Biologics
56 East Bell Drive
P.O. Box 587
Warsaw, Indiana 46581
USA
©2015 Biomet Biologics • Form No. BMET1339.0 • REV0815
www.biomet.com